Journal of Cardiac Failure
Volume 16, Issue 1 , Pages 25-35 , January 2010

Design and Rationale of the PROTECT Study: A Placebo-controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function

  • Beth Davison Weatherley, PhD

      Affiliations

    • Momentum Research, Inc., Durham, NC
    • ,
  • Gad Cotter, MD

      Affiliations

    • Momentum Research, Inc., Durham, NC
    • ,
  • Howard C. Dittrich, MD

      Affiliations

    • NovaCardia, Inc., San Diego, CA
    • Corresponding Author InformationReprint requests: Howard C Dittrich, MD, 12750 High Bluff Drive, Suite 300, San Diego, CA 92130.
    • ,
  • Paul DeLucca, PhD

      Affiliations

    • Merck Research Laboratories, Rahway, NJ
    • ,
  • George A. Mansoor, MD

      Affiliations

    • Merck Research Laboratories, Rahway, NJ
    • ,
  • Daniel M. Bloomfield, MD

      Affiliations

    • Merck Research Laboratories, Rahway, NJ
    • ,
  • Piotr Ponikowski, MD

      Affiliations

    • Klinika Kardiologii, WrocLaw, Poland
    • ,
  • Christopher M. O'Connor, MD

      Affiliations

    • Duke University Medical Center, Durham, NC
    • ,
  • Marco Metra, MD

      Affiliations

    • University of Brescia, Brescia, Italy
    • ,
  • Barry M. Massie, MD

      Affiliations

    • University of California, San Francisco, CA
    • ,
  • PROTECT Steering Committee, Investigators, and Coordinators

Received 22 July 2009 ,Revised 12 October 2009 ,Accepted 27 October 2009.

References 

  1. American Heart Association. Heart disease and stroke statistics—2005 update. Dallas, TX: American Heart Association; 2005;
  2. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update incorporated into the ACCF/AHA 2005 guidelines for the diagnosis and management of chronic heart failure in adults with the 2008 focused update incorporated. Circulation. 2009;119:1977–2016
  3. Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM, O'Connor CM, Metra M, et al. Protect Steering Committee, Investigators, and Coordinators. The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment. J Card Fail. 2008;14:631–640
  4. Dries DL, Exner DV, Domanski MJ, et al. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2000;52:1527–1539
  5. Cody RJ, Ljungman S, Covit AB, et al. Regulation of glomerular filtration rate in chronic congestive heart failure patients. Kidney Int. 1988;34:361–367
  6. Hillege HL, Girbes AR, de Kam PJ, et al. Renal function, neurohormonal activation and survival in patients with chronic heart failure. Circulation. 2000;102:203–210
  7. Vallon V, Muhlbauer B, Osswald H. Adenosine and kidney function. Physiol Rev. 2006;86:901–940
  8. Lucas DG, Hendrick JW, Sample JA, et al. Cardiorenal effects of adenosine subtype 1 (A1) receptor inhibition in an experimental model of heart failure. J Am Coll Surg. 2002;194:603–609
  9. Elkayam U, Mehra A, Cohen G, et al. Renal circulatory effects of adenosine in patients with chronic heart failure. J Am Coll Cardiol. 1998;32:211–215
  10. Dohadwala MM, Givertz MM. Role of adenosine antagonism in the cardiorenal syndrome. Cardiovasc Ther. 2008;24:276–286
  11. Gottlieb SS, Skettino SL, Wolff A, et al. Effects of BG9719 (CVT-124), an A1-adenosine receptor antagonist, and furosemide on glomerular filtration rate and natriuresis in patients with congestive heart failure. J Am Coll Cardiol. 2000;35:56–59
  12. Gottlieb SS. Renal effects of adenosine A1-receptor antagonists in congestive heart failure. Drugs. 2001;61:1387–1393
  13. Gottlieb SS, Brater DC, Thomas I, et al. BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation. 2002;105:1348–1353
  14. Nonaka H, Ichimura M, Takeda M, et al. KW-3902, a selective high affinity antagonist for adenosine A1 receptors. Br J Pharmacol. 1996;117:1645–1652
  15. Slawsky MT, Givertz MM. Rolofylline: a selective adenosine 1 receptor antagonist for the treatment of heart failure. Expert Opin Pharmacother. 2009;10:311–322
  16. Dittrich HC, Gupta DK, Hack TC, et al. The effect of KW-3902, an adenosine A1 receptor antagonist, on renal function and renal plasma flow in ambulatory patients with heart failure and renal impairment. J Card Fail. 2007;13:609–617
  17. Givertz MM, Massie BM, Fields TK, et al. The effects of KW-3902, an adenosine A1-receptor antagonist, on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance. J Am Coll Cardiol. 2007;50:1551–1560
  18. Dunwiddie TV, Worth T. Sedative and anticonvulsant effects of adenosine analogs in mouse and rat. J Pharmacol Exp Ther. 1982;220:70–76
  19. Teerlink JR. Dyspnea as an end point in clinical trials of therapies for acute decompensated heart failure. Am Heart J. 2003;145:S26–S33
  20. Teerlink JR, McMurray JJR, Cotter G, et al. for the VERITAS Investigators. Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials. JAMA. 2007;298:2009–2019
  21. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Card Fail. 2001;7:176–182
  22. Hare JM, Mangal B, Brown J, Fisher C, Freudenberger R, Colucci WS, et al. for the OPT-CHF Investigators. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J Am Coll Cardiol. 2008;51:2301–2309
  23. Abraham WT. Rationale and design of a randomized clinical trial to assess the safety and efficacy of cardiac resynchronization therapy in patients with advanced heart failure: the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). J Card Fail. 2000;6:369–380
  24. Cleland JG, Freemantle N, Coletta AP, et al. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail. 2006;8:105–110
  25. Mitrovic V, Seferovic P, Dodic SS, et al. Cardio-renal effects of the A1 adenosine receptor antagonist SLV320 in patients with heart failure. Presented at the 12th Heart Failure Society of America Annual Scientific Meeting. Toronto: Canada; September 21-24, 2008;

 All decisions regarding this manuscript were made by a guest editor.

 Funded by Merck & Co., Inc., Whitehouse Station, NJ.

 Author Disclosures and Contributions

 Howard C. Dittrich, MD, employee of NovaCardia, Inc, a wholly owned subsidiary of Merck & Co and consultant to Merck & Co (H.C.D.); Piotr Ponikowski, MD: Investigator and Executive Committee member (P.P.); Beth Davison Weatherley PhD: Employee of Momentum Research, Inc, a vendor to Merck & Co (B.D.W.); Marco Metra, MD: Investigator and Executive Committee member (M.M.); John R. Teerlink MD: Chair, Clinical Events Committee (J.R.T.); Gad Cotter MD: Employee of Momentum Research, Inc, a vendor to Merck & Co (G.C.); Paul DeLucca PhD: Employee of Merck & Co (P.D.); George A. Mansoor MD: Employee of Merck & Co (G.A.M.); Daniel M. Bloomfield, MD: Employee of Merck & Co (D.M.B.); Christopher M. O'Connor, MD: Co-Principal Investigator, Consultant to Merck & Co (C.M.O'C.); Barry M. Massie, MD: Co-Principal Investigator, Consultant to Merck & Co (B.M.M.).

 The manuscript was primarily drafted by Drs Dittrich, Ponikowski, Bloomfield, and Massie, with substantial contributions from Drs Weatherley and DeLucca regarding the statistical and analysis plan. The other listed authors reviewed and commented on the manuscript at several stages and approved the final submitted version. No unlisted individuals contributed to the writing of this manuscript.

PII: S1071-9164(09)01146-4

doi: 10.1016/j.cardfail.2009.10.025

Journal of Cardiac Failure
Volume 16, Issue 1 , Pages 25-35 , January 2010

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